The best magazine
Drug development for chronic hepatitis C is progressing at a furious rate; after more than 10 years spent at optimizing Pegylated Interferon and Ribavirin regimens, the ability to design drugs targeting key steps of the HCV life cycle has allowed the development of several directly acting antivirals (DAA). The NS3/4A Protease inhibitors Telaprevir and Boceprevir, have been a major breakthrough for patients and clinicians as they finally allowed patients with HCV genotype 1 to achieve high SVR rates, that top the 80% mark in some highly responsive subgroups. Unfortunately, both drugs did not solve all our problems because of a significant pill burden, clinically relevant drug–drug interactions and most importantly the fact that their efficacy is heavily relying on the activity of the PegIFN/Rbv backbone. This meaning that patients contraindicated to PegIFN/Rbv are still without any effective treatment option, treatment in patients with cirrhosis is less effective than ideal and safety of these regimens is poor in patients with borderline compensated cirrhosis.
Second wave protease inhibitors have either been licensed already (Simeprevir in North America) or are in advanced development study phases (Faldaprevir, Danoprevir and Vaniprevir). These drugs offer several benefits over TVR and BOC, especially in terms of side effect profile and pill burden. Simeprevir is a once-a day oral NS3/4A protease inhibitor with a potent antiviral efficacy on HCV genotypes 1 and 4 in combination with PR. Phase II and III trials in HCV 1 naive patients showed SVR rates ranging from 68 to 76% with this triple therapy regimen, with roughly 80% of subjects eligible to receive the short treatment duration of 24 weeks of therapy. In treatment experienced patients, the SVR rates were dependent on the individual IFN sensitivity, with 85% of previous relapsers, 75% of partial responders and 51% of prior nonresponders reaching an SVR.
In this issue of Liver International, Everson et al. report the results from the DAUPHINE study: a randomized Phase IIb trial of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alfa-2a/ribavirin (P/R) in treatment-naive patients with HCV genotype 1 or 4 infection. Danoprevir/r is a twice-a-day second wave protease inhibitor with antiviral activity against genotype 1, 4 and 6; it is boosted with ritonavir, which leads to strong inhibition of CYP3A activity and increase the PI serum levels. Ritonavir boosting was developed as previous studies reported hepatotoxicity because of reactive metabolites at higher nonboosted doses of Danoprevir. Ritonavir is an inhibitor of the human immunodeficiency virus (HIV)-1 protease. It is a dose- and time-dependent inhibitor/inducer of CYP3A and an inhibitor of P-glycoprotein (P-gp) and is widely used at low, subtherapeutic doses (i.e. 100–400 mg/day) to enhance or 'boost' the exposures of other HIV protease inhibitors that are extensively metabolized by the CYP3A isoenzyme. Danoprevir is primarily metabolized by CYP3A and is a substrate of the P-gp transporter. The current development strategy utilizes the combination of danoprevir with low-dose (100 mg) ritonavir to maximize safety, efficacy and convenience by optimizing danoprevir pharmacokinetics.
The DAUPHINE trial was designed to evaluate three different dosage of Danoprevir/r: 50, 100 and 200 mg danoprevir, boosted with 100 mg ritonavir, assumed twice a day for 24 weeks. A study arm also explored danoprevir/r 100/100 mg, in a Response-guided therapy (RGT) algorithm, in which patients reaching an RVR received a total of 12 weeks of treatment. Treatment safety and efficacy was compared with a placebo-receiving group, the PR arm. Overall the authors observed better SVR rates in higher dosage arms compared to lower dosage arms and the control PR group. SVR rates decreased with decreasing dosage of Danoprevir/r as follows: 89.1%, 78.5% and 69.1%. In the RGT arm overall the SVR rate was 66%, 71.4% in patients with an eRVR2 and 65.8% in patients without an eRVR2. This result was the consequence of higher relapse rates in the RGT arm compared with the other active arms (25% vs. 1.2%, 8.4% and 18%) and the placebo group (20%). HCV genotype 1a emerged as a predictor of treatment failure with SVR rates generally 10 to 15% lower than in HCV-1b. The reason being the lower genetic barrier to resistance of HCV-1a to Danoprevir-resistant mutations. Interleukin 28B genotype was associated with treatment outcome as HCV-1b naïve-infected patients carrying the treatment favourable IL28B CC genotype achieved a 96.6% SVR rates in the highest dosage arm. The role of IL28B CC genotype is relevant also in the RGT arm, where CC patients achieved SVR in 92% of cases. Interestingly, the Danoprevir/r-based regimen reached high SVR rates in HCV-4 patients, a category of patients in whom first generation protease inhibitors are not effective, with 87 to 100% of these patients reaching an SVR, independently from IL28B status. Danoprevir/r showed an acceptable safety profile especially when compared with first generation PIs. Diarrhoea was the only adverse event observed with a higher incidence in active medication arms when compared with placebo arm. The incidence of discontinuation ranged from 2 to 6% across all arms.
The conclusions that we can draw from the DAUPHINE study is that Danoprevir/r, similarly to other second wave PIs, is clearly an improvement compared to first generation PIs, but unfortunately still has many of the same limitations (low genetic barrier to resistance for HCV-1a and efficacy largely based on sensibility to PegIFN) that hampered Telaprevir/Boceprevir. In an era where progress is moving extremely fast and where compelling Phase II and III data have been presented on the efficacy of IFN-free regimens even in hard to cure groups of patients, the innovation carried by a PegIFN/RBV plus second wave PI regimen is hard to foresee. Indeed, we can envision two scenarios for the future of these compounds: either they could be part of a combination of DAAs in an IFN-free combination or they could be chosen based on cost/efficacy ratio in countries where access to IFN-free regimens will probably be limited by national healthcare resources. The first option has been already proven to be effective in a small pilot study of Simeprevir plus Sofosbuvir, a potent NS5B nucleotide polymerase inhibitor with pan-genotypic activity and high genetic barrier to resistance. In the Cosmos study, a 12- or 24-week course of this regimen with or without Ribavrin was able to achieve 93–100% SVR rates in HCV-1 patients, independently from Fibrosis staging and previous treatment status. Faldaprevir was also used as part of an IFN-free regimen in combination with Deleobuvir, an NS5B nonnucleoside polymerase inhibitor, in HCV-1b patients. Although the final results of the phase III study are not yet published, an unexpected rate of treatment discontinuations because of Deleobuvir-related side effects have led to the premature interruption of the development of this combination. Although Danoprevir in combination with the NS5B nucleoside polymerase inhibitor Mericitabine provided the first proof of concept evidence that an IFN free regimen was able to obtain HCV RNA undetectability, to our knowledge this regimen has been disappointing in terms of SVR rates in clinical studies and is not being pushed forward for future developments.
Using second wave PIs containing PegIFN/Rbv regimens for cost/efficacy reasons is another option that is likely to be considered in many countries with a social healthcare system. Given the efficacy of these regimens in some subgroups of patients and the possibility to effectively treat patients with HCV-4 too, this might seem like a reasonable approach to treat patients with low priority to more expensive IFN-free regimens. However, this approach raises the question on whether we as clinicians should aim at granting access to IFN-free regimens to the largest number of patients possible, rather than using slightly less effective and more toxic IFN containing regimens for some of them. This clearly is a hot topic that cannot be solved by the single clinician, but rather requires a co-operative effort from scientific societies, stakeholders, patients associations and pharma-companies to ensure treatment equality based on needs rather than economics.
Source: ...